If they are absent, everything goes wrong. Right from the development of the embryo, the cell adhesion molecules of the cadherin superfamily ensure that cells are bound together while they are developing and when they become adult organisms. Cadherins fix tissue in place and give it shape and identity. But this is far from being all that they do. Dr. Dirk Junghans and his team at the Freiburg University Medical Centre have carried out experiments to show that cell adhesion is also able to mediate important signalling pathways. For example, cadherins regulate the number of neuronal stem cells in the embryonic brain. In addition, they have also been shown to play an important role in cancer.
Cadherins are transmembrane proteins that are anchored to the cytoskeleton of cells and extend into the extracellular space where they bind to the cadherins of other cells. They can fuse entire cell surfaces to each other, just like a zip. This is of great importance for the boundary tissue of many organs. One such an organ is the outer zone of the intestinal wall, which consists of an impermeable layer of closely adhering cells, called intestinal epithelium. This particular structural function of cadherins has for a long time been the only known cadherin function. “Now we know that these molecules are also involved in the regulation of important signalling processes,” said Dr. Dirk Junghans of the Department of Neuroanatomy headed up by Prof. Dr. Michael Frotscher at Freiburg University Medical Centre’s Institute of Anatomy and Cell Biology.
An example of the importance of cadherins is the early development of mice. The developing embryo is barely recognisable as a mouse. At the embyro stage, important decisions have to be made. Which cells are to become the nervous system? Which cells remain stem cells? The cells and stem cells of what is known as neuroepithelium play an important role in these decisions. The neuroepithelium is a cell layer which later becomes the brain. The cells in the neuroepithelium are bound to each other by cadherins. They divide symmetrically to create new stem cells. However, at a specific point in time, these cells divide asymmetrically. One daughter cell remains a stem cell, and the other detaches from the epithelial cell collective and enters the tissue. It develops into a nerve or glial cell and hence becomes part of the brain. Genetic manipulation is used by scientists to block cell adhesion, with the result that the cells of the neuroepithelium lose contact with each other and therefore lose their stem cell character. The embryo then does not develop a brain.
Intensive research is being undertaken to find out whether stem cells divide symmetrically or asymmetrically. “This decision also depends on a signalling pathway that is regulated by molecules of the Wnt family. This signalling pathway regulates the number of stem cells and hence the number of neurons and glial cells,” said Junghans. “Cadherins somehow interact with this signalling pathway, but it is still not known how this interaction works exactly.” Junghans, who originally worked in the field of biochemistry, has focused for many years on signalling pathways such as the Wnt pathway of developing mice and chickens. Junghans and his fellow scientists have a great deal of experience with many methods that enable them to specifically manipulate certain genes and investigate the consequences of such manipulations. The researchers are extremely interested in cadherins because one of the proteins which couples the cadherins to the cytoskeleton inside the cells is ß-catenin. This protein also regulates the Wnt signalling pathway. “Could it be possible that ß-catenin is the molecular switch between the cell adhesion machinery and the molecular networks that turn certain cells into neurons or neuronal stem cells?” asks Junghans. This is a complicated question. The scientists hope to find the answer by specifically switching on and off different components of these two systems.
A collaborative project carried out with a team from the Freiburg-based Max Planck Institute of Immunobiology, is one example of the experiments being conducted. The MPI researchers have recently discovered a gene that normally plays a role in muscles and immune cells. In mouse embryos, the same gene is also a negative regulator of the number of neurons formed. “The lack of this gene causes the animals to develop a huge brain,” said Junghans. Junghans and his team have found out that the protein product of the gene interacts with the components of the cytoskeleton – the same components that also anchor the cadherins inside the cells. Further experiments showed that the gene can also regulate the number of neuronal stem cells in the neuroepithelium: if the gene was switched off, it led to a much larger number of stem cells developed. This also highlights the role of the adhesion system in the destiny of cells. But what exactly is this role?
In principle, cell adhesion molecules can affect the transduction of signals in developing tissue in two ways. First, through their structural role alone: by binding two cells tightly to each other, they reduce the distance between them and enable the exchange of signalling molecules. Second, components of the adhesion machinery can also regulate the transduction of signals themselves, for example the aforementioned ß-catenin. Junghans and his team hope to gain a greater understanding of the correlations in future. This might not just be of interest for basic research in developmental biology, Junghans also envisages potential for medical application. “Cadherins and molecules such as Wnt and ß-catenin play an important role in tumour biology, for example,” said Junghans. If a tumour cell loses the ability to produce E-cadherin, it is able to detach from a solid tumour and migrate. Many cancer researchers assume that this leads to the development of metastases. Junghans also envisages that stem cell research could benefit from further insights into the function of cell adhesion molecules. A potential scenario could be that researchers will learn how to control stem cells using molecular signals. There is a chance that this might enable the regeneration of injured tissue.